Smad7 is required for the development and function of the heart.
Transforming growth factor-beta (TGF-beta) family members, including TGF-betas, activins, and bone morphogenetic proteins, exert diverse biological activities in cell proliferation, differentiation, apoptosis, embryonic development, and many other processes. These effects are largely mediated by Smad proteins. Smad7 is a negative regulator for the signaling of TGF-beta family members. Dysregulation of Smad7 is associated with pathogenesis of a variety of human diseases. However, the in vivo physiological roles of Smad7 have not been elucidated due to the lack of a mouse model with significant loss of Smad7 function. Here we report generation and initial characterization of Smad7 mutant mice with targeted deletion of the indispensable MH2 domain. The majority of Smad7 mutant mice died in utero due to multiple defects in cardiovascular development, including ventricular septal defect and non-compaction, as well as outflow tract malformation. The surviving adult Smad7 mutant mice had impaired cardiac functions and severe arrhythmia. Further analyses suggest that Smad2/3 phosphorylation was elevated in atrioventricular cushion in the heart of Smad7 mutant mice, accompanied by increased apoptosis in this region. Taken together, these observations pinpoint an important role of Smad7 in the development and function of the mouse heart in vivo.
Chen
Qian
Q
Department of Medical and Molecular Genetics, Riley Heart Research Center, Herman B. Wells Center for Pediatric Research, Division of Pediatric Cardiology, and Department of Biochemistry and Molecular Biology, Indiana University School of Medicine and the Walther Cancer Institute, Indianapolis, Indiana 46202, the Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China, and the Department of Medicine, University of California San Diego, La Jolla, California 92093; Department of Medical and Molecular Genetics, Riley Heart Research Center, Herman B. Wells Center for Pediatric Research, Division of Pediatric Cardiology, and Department of Biochemistry and Molecular Biology, Indiana University School of Medicine and the Walther Cancer Institute, Indianapolis, Indiana 46202, the Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China, and the Department of Medicine, University of California San Diego, La Jolla, California 92093.
Chen
Hanying
H
Department of Medical and Molecular Genetics, Riley Heart Research Center, Herman B. Wells Center for Pediatric Research, Division of Pediatric Cardiology, and Department of Biochemistry and Molecular Biology, Indiana University School of Medicine and the Walther Cancer Institute, Indianapolis, Indiana 46202, the Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China, and the Department of Medicine, University of California San Diego, La Jolla, California 92093.
Zheng
Dawei
D
Department of Medical and Molecular Genetics, Riley Heart Research Center, Herman B. Wells Center for Pediatric Research, Division of Pediatric Cardiology, and Department of Biochemistry and Molecular Biology, Indiana University School of Medicine and the Walther Cancer Institute, Indianapolis, Indiana 46202, the Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China, and the Department of Medicine, University of California San Diego, La Jolla, California 92093.
Kuang
Chenzhong
C
Department of Medical and Molecular Genetics, Riley Heart Research Center, Herman B. Wells Center for Pediatric Research, Division of Pediatric Cardiology, and Department of Biochemistry and Molecular Biology, Indiana University School of Medicine and the Walther Cancer Institute, Indianapolis, Indiana 46202, the Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China, and the Department of Medicine, University of California San Diego, La Jolla, California 92093.
Fang
Hong
H
Department of Medical and Molecular Genetics, Riley Heart Research Center, Herman B. Wells Center for Pediatric Research, Division of Pediatric Cardiology, and Department of Biochemistry and Molecular Biology, Indiana University School of Medicine and the Walther Cancer Institute, Indianapolis, Indiana 46202, the Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China, and the Department of Medicine, University of California San Diego, La Jolla, California 92093.
Zou
Bingyu
B
Department of Medical and Molecular Genetics, Riley Heart Research Center, Herman B. Wells Center for Pediatric Research, Division of Pediatric Cardiology, and Department of Biochemistry and Molecular Biology, Indiana University School of Medicine and the Walther Cancer Institute, Indianapolis, Indiana 46202, the Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China, and the Department of Medicine, University of California San Diego, La Jolla, California 92093.
Zhu
Wuqiang
W
Department of Medical and Molecular Genetics, Riley Heart Research Center, Herman B. Wells Center for Pediatric Research, Division of Pediatric Cardiology, and Department of Biochemistry and Molecular Biology, Indiana University School of Medicine and the Walther Cancer Institute, Indianapolis, Indiana 46202, the Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China, and the Department of Medicine, University of California San Diego, La Jolla, California 92093.
Bu
Guixue
G
Department of Medical and Molecular Genetics, Riley Heart Research Center, Herman B. Wells Center for Pediatric Research, Division of Pediatric Cardiology, and Department of Biochemistry and Molecular Biology, Indiana University School of Medicine and the Walther Cancer Institute, Indianapolis, Indiana 46202, the Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China, and the Department of Medicine, University of California San Diego, La Jolla, California 92093.
Jin
Ting
T
Department of Medical and Molecular Genetics, Riley Heart Research Center, Herman B. Wells Center for Pediatric Research, Division of Pediatric Cardiology, and Department of Biochemistry and Molecular Biology, Indiana University School of Medicine and the Walther Cancer Institute, Indianapolis, Indiana 46202, the Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China, and the Department of Medicine, University of California San Diego, La Jolla, California 92093.
Wang
Zhenzhen
Z
Department of Medical and Molecular Genetics, Riley Heart Research Center, Herman B. Wells Center for Pediatric Research, Division of Pediatric Cardiology, and Department of Biochemistry and Molecular Biology, Indiana University School of Medicine and the Walther Cancer Institute, Indianapolis, Indiana 46202, the Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China, and the Department of Medicine, University of California San Diego, La Jolla, California 92093.
Zhang
Xin
X
Department of Medical and Molecular Genetics, Riley Heart Research Center, Herman B. Wells Center for Pediatric Research, Division of Pediatric Cardiology, and Department of Biochemistry and Molecular Biology, Indiana University School of Medicine and the Walther Cancer Institute, Indianapolis, Indiana 46202, the Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China, and the Department of Medicine, University of California San Diego, La Jolla, California 92093.
Chen
Ju
J
Department of Medical and Molecular Genetics, Riley Heart Research Center, Herman B. Wells Center for Pediatric Research, Division of Pediatric Cardiology, and Department of Biochemistry and Molecular Biology, Indiana University School of Medicine and the Walther Cancer Institute, Indianapolis, Indiana 46202, the Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China, and the Department of Medicine, University of California San Diego, La Jolla, California 92093.
Field
Loren J
LJ
Department of Medical and Molecular Genetics, Riley Heart Research Center, Herman B. Wells Center for Pediatric Research, Division of Pediatric Cardiology, and Department of Biochemistry and Molecular Biology, Indiana University School of Medicine and the Walther Cancer Institute, Indianapolis, Indiana 46202, the Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China, and the Department of Medicine, University of California San Diego, La Jolla, California 92093.
Rubart
Michael
M
Department of Medical and Molecular Genetics, Riley Heart Research Center, Herman B. Wells Center for Pediatric Research, Division of Pediatric Cardiology, and Department of Biochemistry and Molecular Biology, Indiana University School of Medicine and the Walther Cancer Institute, Indianapolis, Indiana 46202, the Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China, and the Department of Medicine, University of California San Diego, La Jolla, California 92093.
Shou
Weinian
W
Department of Medical and Molecular Genetics, Riley Heart Research Center, Herman B. Wells Center for Pediatric Research, Division of Pediatric Cardiology, and Department of Biochemistry and Molecular Biology, Indiana University School of Medicine and the Walther Cancer Institute, Indianapolis, Indiana 46202, the Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China, and the Department of Medicine, University of California San Diego, La Jolla, California 92093; Department of Medical and Molecular Genetics, Riley Heart Research Center, Herman B. Wells Center for Pediatric Research, Division of Pediatric Cardiology, and Department of Biochemistry and Molecular Biology, Indiana University School of Medicine and the Walther Cancer Institute, Indianapolis, Indiana 46202, the Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China, and the Department of Medicine, University of California San Diego, La Jolla, California 92093; Department of Medical and Molecular Genetics, Riley Heart Research Center, Herman B. Wells Center for Pediatric Research, Division of Pediatric Cardiology, and Department of Biochemistry and Molecular Biology, Indiana University School of Medicine and the Walther Cancer Institute, Indianapolis, Indiana 46202, the Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China, and the Department of Medicine, University of California San Diego, La Jolla, California 92093. Electronic address: wshou@iupui.edu.
Chen
Yan
Y
Department of Medical and Molecular Genetics, Riley Heart Research Center, Herman B. Wells Center for Pediatric Research, Division of Pediatric Cardiology, and Department of Biochemistry and Molecular Biology, Indiana University School of Medicine and the Walther Cancer Institute, Indianapolis, Indiana 46202, the Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China, and the Department of Medicine, University of California San Diego, La Jolla, California 92093. Electronic address: ychen3@sibs.ac.cn.
D000595:Amino Acid Sequence; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000235:genetics / Q000378:metabolism; D006321:Heart / Q000196:embryology*; D006330:Heart Defects, Congenital / Q000235:genetics / Q000378:metabolism; D006801:Humans; D051379:Mice; D008817:Mice, Mutant Strains; D010766:Phosphorylation / Q000235:genetics; D017434:Protein Structure, Tertiary / Q000235:genetics; D017384:Sequence Deletion; D051899:Smad2 Protein / Q000235:genetics / Q000378:metabolism; D051900:Smad3 Protein / Q000235:genetics / Q000378:metabolism; D051906:Smad7 Protein / Q000235:genetics / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism
D051899:Smad2 Protein; C497783:Smad2 protein, mouse; D051900:Smad3 Protein; C497791:Smad3 protein, mouse; D051906:Smad7 Protein; C497807:Smad7 protein, mouse; D016212:Transforming Growth Factor beta